Dichloromethane → (S)-4-(2-chloro-9-ethyl-8-(pyrimidin-5-yl)-9H-purin-6-yl)-3-methylmorpholine

HRID 2063375Notes

Reaction equation

HRID 2063375 reaction equation
[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](I)[N:8]2[CH2:11][CH3:12])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].ClCCl>C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].Cl[Pd]Cl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)[N:8]2[CH2:11][CH3:12])=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][C@@H:15]2[CH3:20])[N:3]=1

Participants

7

Reactant 4

HCID 6344DichloromethaneHCID 62657Potassium Phosphate, TribasicHCID 4192667Pyrimidine-5-boronic acid, pinacol esterHCID 58222524(S)-4-(2-chloro-9-ethyl-8-iodo-9H-purin-6-yl)-3-methylmorpholine

Product 1

HCID 58222540(S)-4-(2-chloro-9-ethyl-8-(pyrimidin-5-yl)-9H-purin-6-yl)-3-methylmorpholineYield 77.8%

Reagents, catalysts & solvents 2

HCID 24290Palladium ChlorideCatalystHCID 635956Ferrocene-1,1'-bis-(diphenylphosphine)Catalyst

Conditions

Temperature
120 °C

Procedure

In a 5-mL microwave vessel equipped with a stirbar was placed (S)-4-(2-chloro-9-ethyl-8-iodo-9H-purin-6-yl)-3-methyl-morpholine (30 mg, 0.074 mmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine (22.7 mg, 0.110 mmol, 1.5 eq.), potassium phosphate (46.9 mg, 0.22 mmol, 3.0 eq.), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (1:1) (3.0 mg, 0.0037 mmol, 0.05 eq.), and degassed 1,4-dioxane (3.0 mL). The microwave tube was capped, and the reaction mixture was heated under microwave irradiation (300 watts, 120° C.) for 15 minutes. The reaction mixture was diluted with ethyl acetate (10 mL) and filtered through a pad of Celite. The organic layer was washed with water and brine, then dried (Na2SO4), filtered and evaporated in vacuo. The resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in heptane) to give the desired compound (k-1) as a foam (20.6 mg, 77.8%). 1H NMR (CDCl3, 400 MHz) δ ppm 9.34 (s, 1H), 9.13 (s, 2H), 6.00 to 4.60 (broad s, 2H), 4.42 to 4.28 (m, 2H), 4.11 to 3.97 (m, 1H), 3.87 to 3.72 (m, 2H), 3.71 to 3.59 (m, 1H), 3.59 to 3.40 (broad s, 1H), 1.51 to 39 (m, 6H); LC-MS m/z (method A): RT=2.21 min, [M+H]+=360.

Workup

  1. customIn a 5-mL microwave vessel equipped with a stirbar
  2. customdegassed 1,4-dioxane (3.0 mL)
  3. customThe microwave tube was capped
  4. additionThe reaction mixture was diluted with ethyl acetate (10 mL)
  5. filtrationfiltered through a pad of Celite
  6. washThe organic layer was washed with water and brine
  7. dry with materialdried (Na2SO4)
  8. filtrationfiltered
  9. customevaporated in vacuo
  10. customThe resultant residue was purified by column chromotagraphy (Si-PPC, gradient 0 to 100% ethyl acetate in heptane)

Sources & evidence

ORD record
ord-b3d085999be648059b512625393b0c95
Source dataset
uspto-grants-2012_10
Patent number
US08288381B2

Reaction notes

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